Process for the preparation of isocarbostyrils

ABSTRACT

Isocarbostyrils are conveniently prepared in high yields and in a high degree of purity by contacting an isoquinoline with an anhydrous, liquid melt mixture of potassium hydroxide and sodium hydroxide. The anhydrous, melt mixture is prepared by reacting potassium hydroxide with an amount of sodium oxide sufficient to consume all the water present and then heating the mixture to its melting point. Thereafter the isoquinoline is added and upon completion of the reaction, water is introduced to hydrolyze the potassium isocarbostyril salt. Isocarbostyrils are useful as intermediates in the production of dyes, pharmaceuticals, antioxidants, and surfactants.

United States Patent 1 91 Lenaers et al.

[ Feb. 13, 1973 PROCESS FOR THE PREPARATION OF ISOCARBOSTYRILS [73]Assignee: Union Carbide Corporation, New

York, N.Y.

[22] Filed: Dec. 23, 1970 21 Appl.No.: 101,146

[52] US. Cl. ..260/289 R, 260/283 R, 260/283 S,

260/286 R [51 Int. Cl. ..C07d 35/30 [58] Field of Search ..260/289 R,326.5 FM, 239.3

Primary Examiner-Donald G. Daus. Attorney-Raul A. Rose, Harrie M.l-lumphreys and William R. Moran l 5 7 ABSTRACT lsocarbostyrils areconveniently prepared in high yields and in a high degree of purity bycontacting an isoquinoline with an anhydrous, liquid melt mixture ofpotassium hydroxide and sodium hydroxide.

The anhydrous, melt mixture is prepared by reacting potassium hydroxidewith an amount of sodium oxide sufficient to consume all the waterpresent and then heating the mixture to its melting point. Thereafterthe isoquinoline is added and upon completion of the reaction, water isintroduced to hydrolyze the potassium isocarbostyril salt.Isocarbostyrils are useful as intermediates in the production of dyes,pharmaceuticals, antioxidants, and surfactants.

10 Claims, No Drawings PROCESS FOR THE PREPARATION OF ISOCARBOSTYRILSThis invention relates to a process for the preparation ofisocarbostyrils. In one aspect, this invention is directed to thepreparation of isocarbostyrils in high yields and in a high degree ofpurity. in a further aspect, this invention is directed to thepreparation of isocarbostyrils which are useful intermediates in thesynthesis of known organic compounds.

Various methods have been reported in the literature for the productionof isocarbostyrils. One of the earliest methods reported was the work ofA. E. Chichibabin et al., Journ. Pricladnoi Fiziceskogo ChimiceskogoObchestva, tome LXIl, vol. 5, 1211/6 1930 which used solid potassiumhydroxide and isoquinoline to produce isocarbostyril. The reaction,however, was irregular and the product had to be purified. Moreover, thepreparation of powdered calcinated" potassium hydroxide required specialfacilities. More recently, other methods have been devised for thepreparation of isocarbostyrils. For example, M.M. Robison et al, J. Org.Chem. 21, 1337 1957 reported the preparation of isocarbostyril by atwo-step synthesis involving the preparation of the N-oxide ofisoquinoline. The method involved the use of large amounts of solventsand had an overall yield of 30-35 percent.

In 1962, V. Georgian et al reported in J. Org. Chem. 27, 4571 (1962) aprocess for hydrolyzing isoquinoline-S-sulfonic acid into -hydroxyisoquinoline using a mixture of potassium hydroxide and sodiumhydroxide. The process was applied only to isoquinoline-S-sulfonic acidand not to other derivatives, including isoquinoline itself. It hassince been observed that the process cannot be applied successfully toisoquinoline itself or most other derivatives unless the alkali melt isfree of water. This involves heating the mixture at least to 475-500C.before introducing the isoquinoline. It thus appeared that the reactionwith isoquinoline sulfonic acid was unique and did not require theremoval of moisture. Recent attempts, however, to prepareisocarbostyrils using technical or analytical grade potassium hydroxidewhich is not moisture-free have been largely unsuccessful. Thepreparation of large amounts of moisture-free potassium hydroxide hasrendered the earlier processes unsuitable when large scale quantities ofisocarbostyrils are desired.

It is therefore an object of this invention to provide a process for thepreparation of isocarbostyrils. Another object of this invention is toprovide a process for the preparation of isocarbostyrils in high yieldsand in a high degree of purity. A further object of the invention is toprovide a process which can be conducted in'a continuous manner. A stillfurther object of the invention is to provide a product which issufficiently pure to be used without additional purification. A furtherobject of the invention is to provide a process which can be conductedat relatively low temperatures. These and other objects will readilybecome apparent to those skilled in the art in the light of theteachings herein set forth.

In its broad aspect, the invention is directed to a novel process forthe preparation of isocarbostyrils. In particular, the preferredisocarbostyrils which can be prepared by the instant process are thoserepresented by the formula:

wherein R represents hydrogen, hydroxy or lower alkyl. Also two adjacentR groups can together with the carbon atoms to which they are attachedform a six-membered hydrocarbon ring. The process comprises the stepsof:

a. contacting in an inert atmosphere i. an anhydrous liquid melt mixturecomprised of potassium hydroxide and sodium hydroxide, said melt havingbeen prepared by reacting potassium hydroxide with an amount of sodiumoxide at least sufficient to consume essentially all the water presentin the potassium hydroxide, and then heating the reaction product of the'potassium hydroxide and sodium oxide to its melting point, and

ii. an isoquinoline of the formula:

wherein R is as above, and R represents hydrogen,

lower alkyl or the sulfonic acid group,

b. hydrolyzing the isocarbostyril salt thus formed,

and

c. recovering the isocarbostyril in a high yield and in a high degree ofpurity.

The process of this invention provides a convenient method for thepreparation of isocarbostyrils in high yields and in a high degree ofpurity. In contrast to the known prior art methods, the mixture ofpotassium hydroxide and sodium hydroxide is formed in situ by theaddition of sodium oxide to potassium hydroxide. This technique servesthe dual purpose of removing essentially all of the water contained inthe potassium hydroxide and proving sodium hydroxide as a result of theinteraction of sodium oxide and water. A major advantage of this processis that the necessity for drying a mixture of potassium hydroxide andsodium hydroxide is eliminated. It has been observed that if a mixtureof potassium and sodium hydroxide is used initially it must becalcinated at relatively high temperatures, i.e., about 500C. for atleast one-quarter of an hour to insure removal of the last traces ofwater. If the water is not completely removed, the yield ofisocarbostyril falls off sharply. For example, it has been observed thatwhen a eutectic melt of potassium and sodium hydroxide is firstcalcinated at 475C. for about 15 minutes, then a yield of isocarbostyrilas high as percent can be obtained. However, if the mixture is merelyheated to about 240C. and the isoquinoline added, no isocarbostyril isrecovered. Hence, the present process, avoids the necessity for heatingthe mixture to high temperature since removal of water and thegeneration of sodium hydroxide are effected simultaneously.

In practice, the amount of sodium oxide employed in preparing theanhydrous melt mixture need. only be that amount which is sufficient toreact with all the water contained in the potassium hydroxide. Asindicated, the sodium oxide reacts with the water forming sufficientsodium hydroxide to render the mixture liquid at temperatures of fromabout 200 to about 250C.

For example, 120 grams 1.9 mole of a technical grade potassium hydroxidecontaining per cent of water 18 grams, 1 mole was treated with 62 grams2 moles of sodium oxide giving 80 grams 2 moles of sodium hydroxide.This mixture which contained about 50 mole percent of potassiumhydroxide and sodium hydroxide melted at about 200 to about 210C. lt hasbeen observed that mixtures containing between about and about 55 molepercent of-potassium hydroxide become liquid at relatively lowtemperature and hence, are suitable for use in the process of thisinvention. No noticeable adverse effects were observed when an excess ofsodium oxide was employed.

ln general, after the mixture becomes liquid and reaches a temperaturewithin the range of from about 200 to about 250C., the isoquinoline isgradually added while the mixture is stirred. The reaction is usuallycompleted when the evolution of hydrogen ceases. Thereafter the mixtureis cooled to about 200C. and water carefully added dropwise to thereaction vessel until the material is pastelike. Thereafter the materialis poured into ice water and the insoluble isocarbostyril filtered,washed with 0.5N HCl 'and water, and dried.

in practice, the reaction is conducted in an. inert atmosphere, such asnitrogen, argon or the like.

lsocarbostyrils prepared by the process of this invention have beenfound to be highly pure and are obtained in relatively high yields. Forexample, if the starting isoquinoline is relatively pure, theisocarbostyril is obtained in about the same degree of purity. Moreover,yields as high as 83 percent and higher of isocarbostyril have beenobtained by the process of this invention.

A wide variety of isocarbostyrils can be prepared by the process of thisinvention. In addition to isocarbostyril itself, illustrative compoundswhich can be prepared include, among others, 3-methylisocarbostyril,3-ethylisocarbostyril, 3-propylisocarbostyril,

3-butylisocarbostyril, 7-rnethylisocarbostyril, 7- ethylisocarbostyril,7-p'ropylisocarbostyril, 8 methylisocarbostyril 8-propylisocarbostyril,8 -butylisocarbostyril 3,7-dimethylisocarbostyril,

5,7dimethylisocarbostyril, S-hydroxyisocarbostyril, 7-hydroxyisocarbostyril, and the like.

' As previously indicated, the starting material, in most instances, isthe corresponding isoquinoline. For example, isoquinoline itself is usedto prepare isocarbostyril. The other compounds listed above are preparedrespectively from 3-methylisoquinoline, 3- ethylisoquinoline,3-propylisoquinoline, 3-butylisoquinoline, 7-methylisoquinoline,7-ethylisoquinoline, 7-propylisoquinoline, 8-methylisoquinoline, 8-propylisoquinoline, S-butylisoquinoline, 3,7- dimethylisoquinoline,5,7-dimethylisoquinoline, 5- isoquinoline sulfonic acid,7-isoquinolinesulfonic acid, and the like.

The isocarbostyrils prepared by the process of this invention are auseful class of compounds having utility in a wide variety of fields.For example, it is known that isocarbostyrils are useful asintermediates in such areas as the production of dyes, pharmaceuticals,antioxidants, surfactants and the like.

The following examples are illustrative EXAMPLE 1 Preparation ofisocarbostyril A mixture of 336 grams of technical grade KOH and 186grams of Na o was introduced into a steel reaction vessel which washeated with an oil bath. The mixture was then heated up to 220-230C.,carefully stirred, and 582 grams of isoquinoline where then introduced.The evolution of hydrogen was immediate and was terminated after a fewminutes. When the reaction was finished, the oil bath was cooled up toabout 200C. and then water was carefully added and the hot alkalinesolution was poured out on ice water where the potassium salt ofisocarbostyril hydrolyzed. The mixture was slightly acidified with HCland the isocarbostyril was filtered, washed with water and dried. Theyield of isocarbostyril was 83 percent and the product had a meltingpoint of 210C. Analysis confirmed the identify of the product.

EXAMPLE 2 Preparation of 3-methylisocarbostyril in a manner similar tothat employed in Example 1 above, a mixture of 448 grams of KOH and 248grams of Na O was introduced into the reaction vessel and heated to220-230C. While carefully stirring the melted mixture 858 grams of3-methylisoquinoline were added. When the reaction was completed, theoil bath was cooled to about 200C. and water added. After pouring thehot alkali solution on ice water, acidifying, and filtering as inExample I above, the 3- methylisocarbostyril was washed with water anddried. The product had a melting point of 214C. and was recovered in ayield of 76 percent.

EXAMPLE 3 Preparation of S-hydroxyisocarbostyril In a manner similar tothat employed in the previous examples, a mixture of H2 grams of KOH and77 grams of Na O wasadded to the reaction vessel and heated to 220-230C.While stirring, 98 grams of S- isoquinoline sulfonic acid were added.Upon completion of the reaction the oil bath was cooied toabout 200C.and water added. The hot alkali solution was poured on ice water,acidified and filtered as in the previous examples. After washing anddrying S-hydroxyisocarbostyril having a melting point of 266C. wasrecovered in a yield of 66 percent.

EXAMPLE 4 Preparation of isocarbostyril from a mixture of potassiumhydroxide and sodium hydroxide Nine hundred twenty-five grams ofpotassium hydroxide and 375 grams of sodium hydroxide were calcinated at475C. for 15 minutes in a 5-liter stainless steel reaction vessel underan atmosphere of nitrogen. The alkali melt was then cooled to 240C. andheld at this temperature by an oil bath. While stirring vigorously,1,500 grams of isoquinoline were slowly added over a period of 2 hoursand 35 minutes. The oil bath was then allowed to cool. When itstemperature reached 200C. water was introduced dropwise into thereaction vessel. The water was absorbed by the alkali melt and decreasedits solidification temperature. A]- together 2,000 milliliters of waterwere added over a period of one hour, at which time the temperature ofthe oil bath was 80C. The reaction vessel was then opened and thecontents, a pastlike material, was poured into liters of water. Theinsoluble isocarbostyril was filtered, washed with 0.5N HCl and waterand dried. There was obtained 1,640 grams of isocarbostyril having amelting point of 208209C. Analysis of the product confirmed it to beisocarbostyril.

When the calcination at 475C. to remove water was omitted and themixture merely heated to 240C, no isocarbostyril was recovered.

Although the invention has been illustrated by the preceding examples itis not to be construed as being limited to the materials employedtherein, but rather, the invention encompasses to the generic area ashereinbefore disclosed. Various modifications of this invention can bemade without departing from the spirit and scope thereof.

What is claimed is:

l. A process for the preparation of isocarbostyrils of the formula:

R R R @R R NH R ii wherein R represents a member selected from the groupconsisting of hydrogen, or not more than 2 R groups represent hydroxyand lower alkyl of up to four carbon atoms, and wherein two adjacent Rgroups can, together with the carbon atoms to which they are attached,form a six-membered hydrocarbon ring, said process consistingessentially of the steps of:

a. contacting, in an inert atmosphere:

i. an anhydrous liquid melt mixture comprised of potassium hydroxide andsodium hydroxide, said melt having been prepared by reacting potassiumhydroxide with an amount of sodium oxide at least sufficient to consumeessentially all the water present in said potassium hydroxide, and thenheating said potassium hydroxide and sodium oxide mixture to its meltingpoint, and

ii. an isoquinoline of the formula:

l l U N wherein R is as above, and R represents a member selected fromthe group consisting of hydrogen,

lower alkyl of up to four carbon atoms or the sulfonic acid group b.hydrolyzing the isocarbostyril salt thus formed,

and

c. recovering said isocarbostyril in a high degree of purity.

2. The process of claim 1 wherein said inert atmosphere is nitrogen.

3. The process of claim 1 wherein said liquid melt mixture is at atemperature of from about 200 to about 250C.

4. The process of claim 1 wherein said liquid melt mixture is comprisedof from about 20 to about 55 mole percent of potassium hydroxide.

5. The process of claim 1 wherein said liquid melt mixture is comprisedof about 50 mole percent of potassium hydroxide and sodium hydroxide.

6. The process of claim 1 wherein said liquid melt mixture is a eutecticmixture of potassium hydroxide and sodium hydroxide.

7. The process of claim 1 wherein an excess of sodium oxide is presentin said melt.

8. The process of claim 1 wherein said potassium hydroxide and sodiumoxide mixture has a melting point of from about 200 to about 250C.

9. The process of claim 1 wherein each of said R groups representshydrogen.

10. In a process for the preparation of isocarbostyrils by contactingisoquinolines with a liquid melt mixture of potassium hydroxide andsodium hydroxide, the improvement which consisting essentially ofpreparing said melt by reacting potassium hydroxide with an amount ofsodium oxide at least sufficient to consume all the water present insaid potassium hydroxide, and then heating said potassium hydroxide andsodium oxide mixture to its melting point.

1. A process for the preparation of isocarbostyrils of the formula:wherein R represents a member selected from the group consisting ofhydrogen, or not more than 2 R groups represent hydroxy and lower alkylof up to four carbon atoms, and wherein two adjacent R groups can,together with the carbon atoms to which they are attached, form asix-membered hydrocarbon ring, said process consisting essentially ofthe steps of: a. contacting, in an inert atmosphere: i. an anhydrousliquid melt mixture comprised of potassium hydroxide and Sodiumhydroxide, said melt having been prepared by reacting potassiumhydroxide with an amount of sodium oxide at least sufficient to consumeessentially all the water present in said potassium hydroxide, and thenheating said potassium hydroxide and sodium oxide mixture to its meltingpoint, and ii. an isoquinoline of the formula: wherein R is as above,and R1 represents a member selected from the group consisting ofhydrogen, lower alkyl of up to four carbon atoms or the sulfonic acidgroup b. hydrolyzing the isocarbostyril salt thus formed, and c.recovering said isocarbostyril in a high degree of purity.
 2. Theprocess of claim 1 wherein said inert atmosphere is nitrogen.
 3. Theprocess of claim 1 wherein said liquid melt mixture is at a temperatureof from about 200* to about 250*C.
 4. The process of claim 1 whereinsaid liquid melt mixture is comprised of from about 20 to about 55 molepercent of potassium hydroxide.
 5. The process of claim 1 wherein saidliquid melt mixture is comprised of about 50 mole percent of potassiumhydroxide and sodium hydroxide.
 6. The process of claim 1 wherein saidliquid melt mixture is a eutectic mixture of potassium hydroxide andsodium hydroxide.
 7. The process of claim 1 wherein an excess of sodiumoxide is present in said melt.
 8. The process of claim 1 wherein saidpotassium hydroxide and sodium oxide mixture has a melting point of fromabout 200* to about 250*C.
 9. The process of claim 1 wherein each ofsaid R groups represents hydrogen.